The sensitivity to acute alcohol intoxication is far more commonly found in Orientals than in Caucasians. The difference is thought to be related to genetic differences in the enzymes involved in alcohol metabolism. It has been suggested that the high frequency in alcohol sensitivity could be due to the rapid acetaldehyde formation by the atypical alcohol dehydrogenase ADH2/2 with high activity which is common among Orientals, or due to the accumulation of acetaldehyde caused by the absence of one of the major aldehyde dehydrogenase isozymes (ALDH-2) with high affinity to acetaldehyde in many Orientals. We recently determined the active site structures of the usual ADH1/2 and atypical ADH2/2. We also demonstrated that the absence of ALDH-2 in many Orientals is not due to gene deletion, nonsense mutation or regulatory mutation, but it is due to a structural mutation producing an enzymatically inactive but immunologically homologous protein. The proposed project includes: a) Study of kinetic properties and active site structures of other usual and atypical alcohol dehydrogenase isozymes controlled by ADH1, ADH2, and ADH3, loci, and b) study of active site structures of two major aldehyde dehydrogenase isozymes, i.e., ALDH-1 and ALDH-2, and the structure of the enzymatically inactive defective protein existing in an atypical Oriental liver. These studies will extend our knowledge on the structure-function relationships of the two dehydrogenases, and may contribute to our understanding of the process of evolutional divergence of the usual and atypical enzymes related to alcohol metabolism in Caucasians and Orientals.